The objective of this invention is to suggest a new molecule which could enter into a therapeutic process for cancers, in particular leukaemias and myeloproliferative neoplasms. Leukaemias and myeloproliferative neoplasms are currently the most frequent cases of cancer with high mortality in men younger than 40 years old and in women younger than 20 years old. One of the recognised markers of these diseases is the malfunction of the transcription factor (TF) Signal Transducer and Activator of Transcription 5 (STAT5) which refers to two proteins, STAT5A and STAT5B which belong to the STAT family of proteins comprising 7 members. STAT5A and STAT5B proteins are encoded by 2 separate genes but their amino acid sequence is identical by more than 90%. STAT5 proteins are involved in cytosolic signalling pathways. Studies have shown that a malfunction of the activity of STAT5A and STAT5B could contribute to the induction of human cancers.
The activation of STAT5B proteins is frequently found in cases of haematological malignancies. In this context, STAT5B protein has been shown as being responsible for leukemogenesis (Benekli et al, 2003 Blood. 101 (8), 2940-54). Studies have also shown that STAT5 transcription factors were activated by a wide spectrum of ligands allowing them to intervene in the physiological and pathophysiological regulation of major biological functions such as cell proliferation, cell differentiation or apoptosis. STAT5B protein therefore constitutes a promising target for new anti-cancer treatments. From an application point of view, the obtaining of molecules that inhibit the activity of STAT5B protein is all the more so important when it is known that the current treatments are not very specific and cause undesirable side effects.
Indeed, treatments such as radiation or chemotherapy are heavy treatments that require long hospital stays in certain cases. Certain patients develop a resistance to the pharmacological inhibitor Imatinib mesylate (or Glivec®—Novartis) currently used as a first line clinically in certain cases of leukaemia. It is therefore indispensable to develop new compounds that make it possible to treat these diseases.
STAT5 inhibitors have already been developed such as AZD1480 but it is also an inhibitor of STAT3 and has side effects. Pimozide inhibits STAT5 but is also a dopamine receptor antagonist and consequently an antipsychotic (Nelson E A Genes Cancer 2012 July; 3(7-8):503-11). Antisenses for STAT5 AB have been tested in vitro in fundamental work but have not yet been developed or tested in clinical trials (Behbod F 2003 J Immunol 171(8):3919-27; Futami M Leukaemia. 2008 June; 22(6):1131-8; Page B D et al 2011 J Med Chem. 2012 Feb. 9; 55(3):1047-55).
In this invention, new specific aptamers of STAT5 protein are described. These aptamers have the advantage of inhibiting STAT5 protein as far downstream as possible of the signalling pathway so as to prevent undesirable side effects that could be linked to the inhibition of the expression of STAT5 protein. Indeed, STAT5 protein is involved in various processes and at different levels in the signalling pathways and the globalised inhibition thereof could be deleterious for the cell. The molecules also have the advantage of being highly specific for the targeted protein, and poorly immunogenic, and demonstrate effective anti-proliferative and pro-apoptotic properties (see the examples).